Epithelial ovarian cancer (EOC) is considered the most lethal gynecologic malignancy and a leading cause of cancer death in Western industrialized countries including the United States. The majority of ovarian cancer cases are high-grade serous ovarian cancers (HGSCs). Unfortunately, the majority of women are diagnosed with advanced stage disease. Despite surgical advances, novel anti-angiogenic targeted therapies, and improved median survival, few women with HGSCs are cured (Berchuck, Iversen et al. 2009). There is an urgent need to develop innovative and rationally directed therapies to improve outcome in women with this disease.
Many promising biologic agents target tumor angiogenesis, a critical component of solid tumor growth and metastasis (Folkman 1994, Folkman 2002). Angiogenesis has been shown to be an important predictor of tumor behavior in a number of human malignancies and can be measured via microvessel density (MVD) counts. MVD microscopic measurement is an established technique, and known prognostic factor (Weidner, Semple et al. 1991, Weidner, Folkman et al. 1992, Weidner, Carroll et al. 1993, Zatterstrom, Brun et al. 1995, de Jong, van Diest et al. 2000, Hlatky, Hahnfeldt et al. 2002). We and others, previously demonstrated that angiogenesis based on MVD has prognostic significance in EOC. Specifically, women whose ovarian cancers demonstrated higher MVD have a worse survival compared to those with lower counts. (Alvarez, Krigman et al. 1999, Rubatt, Darcy et al. 2009). Furthermore, antiangiogenic therapy with inhibitors of vascular endothelial growth factor (VEGF), a potent proangiogenic factor, has demonstrated anti-tumor activity in women with EOC. (Burger 2007). The antiangiogenic agents studied in EOC include agents such Bevacizumab, an anti vascular endothelial growth factor (VEGF) monoclonal antibody, and multitargeted antiangiogenic tyrosine kinase inhibitors such as BIBF 1120 and Pazopanib. (Teoh and Secord 2012).
The VEGF inhibitor, bevacizumab, has been shown to have activity in ovarian cancer as manifested by a response rate of 20% and a 6-month progression-free survival (PFS) rate of 40% (Burger 2007). Two pivotal phase III trials have demonstrated that bevacizumab combined with chemotherapy followed by maintenance bevacizumab yielded a PFS benefit. In a subset analysis of ICON7, the addition of concurrent and maintenance bevacizumab resulted in improved PFS and overall survival in women with suboptimally debulked stage III disease and stage IV disease. (Perren, Swart et al. 2010, Burger 2011, Teoh and Secord 2012). Despite, initial anti-tumor activity, cancers eventually develop resistance to VEGF-blockade. The mechanism of resistance to VEGF inhibitors has not been completely elucidated. One hypothesis maintains that multiple alternate proangiogenic pathways overcome VEGF inhibition and maintain the proangiogenic tumor environment. (Loges, Schmidt et al. 2010). In order to effectively overcome anti-VEGF resistance, novel alternate targets must be elucidated. Moreover, biomarkers are needed to identify ovarian cancer patients that are most likely to benefit from anti-angiogenic-specific therapy in order to minimize toxicity and cost.
High-grade serous ovarian carcinoma (HGSC) is an aggressive type of epithelial ovarian cancer associated with numerous genetic alterations and poor survival. There remains an urgent unmet need for methods that are predictive of clinical outcome in women with this disease to enable rationally directed therapies to improve outcome in these women. The present disclosure provides such compositions and methods.